QT length during methadone maintenance treatment: gene × dose interaction

El Hadi Zerdazi; Florence Vorspan; Andries T. Marees; François Naccache; Jean Pierre Lepine; Jean Louis Laplanche; Nathalie Prince; Cynthia Marie-Claire; Frank Bellivier; Stéphane Mouly; Vanessa Bloch

doi:10.1111/fcp.12405

QT length during methadone maintenance treatment: gene × dose interaction

El Hadi Zerdazi^*, Florence Vorspan, Andries T. Marees, François Naccache, Jean Pierre Lepine, Jean Louis Laplanche, Nathalie Prince, Cynthia Marie-Claire, Frank Bellivier, Stéphane Mouly, Vanessa Bloch

^*Corresponding author for this work

Economics

Research output: Contribution to Journal › Article › Academic › peer-review

22 Downloads (Pure)

Abstract

Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r _Pearson = 0.26; P = 10 ⁻³ ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10 ⁻⁴ ; p _corrected = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (p _empirical = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients’ genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

Original language	English
Pages (from-to)	96-106
Number of pages	11
Journal	Fundamental and Clinical Pharmacology
Volume	33
Issue number	1
Early online date	7 Aug 2018
DOIs	https://doi.org/10.1111/fcp.12405
Publication status	Published - Feb 2019

Funding

METHADOSE study, OST07013 was funded by the DRC (Direction de la Recherche Clinique) of the Assistance Publique—Hôpitaux de Paris). F.V. was also funded by: the Mission Interministerielle de Lutte contre la Drogue & la Toxicomanie (MILDT)—Institut National de la Sante & la Recherche Medicale (INSERM; grant ASE07082KSA) and by the BioPsy Laboratory of Excellence; this work was therefore supported by French state funds managed by the ANR within the Investissements d’Avenir program under reference ANR-11-IDEX-0004-02.

Funders	Funder number
ANR-11-IDEX-0004-02
BioPsy Laboratory of Excellence
Direction de la Recherche Clinique
Institut National de la Sante & la Recherche Medicale
Mission Interministerielle de Lutte contre la Drogue & la Toxicomanie
Diabetes Research Center
Agence Nationale de la Recherche
Institut national de la santé et de la recherche médicale	ASE07082KSA
Assistance Publique - Hôpitaux de Paris	OST07013

Keywords

KCNE1
methadone
QT prolongation
rs11911509

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1111/fcp.12405

QT length during methadone maintenance treatment gene dose interactionFinal published version, 570 KBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Persistent link

Cite this

@article{c8fbcaa5b68f4eb18812663afbe90524,

title = "QT length during methadone maintenance treatment: gene × dose interaction",

abstract = " Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r Pearson = 0.26; P = 10 −3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10 −4 ; p corrected = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (p empirical = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients{\textquoteright} genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment. ",

keywords = "KCNE1, methadone, QT prolongation, rs11911509",

author = "Zerdazi, {El Hadi} and Florence Vorspan and Marees, {Andries T.} and Fran{\c c}ois Naccache and Lepine, {Jean Pierre} and Laplanche, {Jean Louis} and Nathalie Prince and Cynthia Marie-Claire and Frank Bellivier and St{\'e}phane Mouly and Vanessa Bloch",

year = "2019",

month = feb,

doi = "10.1111/fcp.12405",

language = "English",

volume = "33",

pages = "96--106",

journal = "Fundamental and Clinical Pharmacology",

issn = "0767-3981",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "1",

}

TY - JOUR

T1 - QT length during methadone maintenance treatment: gene × dose interaction

AU - Zerdazi, El Hadi

AU - Vorspan, Florence

AU - Marees, Andries T.

AU - Naccache, François

AU - Lepine, Jean Pierre

AU - Laplanche, Jean Louis

AU - Prince, Nathalie

AU - Marie-Claire, Cynthia

AU - Bellivier, Frank

AU - Mouly, Stéphane

AU - Bloch, Vanessa

PY - 2019/2

Y1 - 2019/2

N2 - Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r Pearson = 0.26; P = 10 −3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10 −4 ; p corrected = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (p empirical = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients’ genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

AB - Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r Pearson = 0.26; P = 10 −3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10 −4 ; p corrected = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (p empirical = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients’ genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

KW - KCNE1

KW - methadone

KW - QT prolongation

KW - rs11911509

UR - http://www.scopus.com/inward/record.url?scp=85060163845&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060163845&partnerID=8YFLogxK

U2 - 10.1111/fcp.12405

DO - 10.1111/fcp.12405

M3 - Article

C2 - 30086202

AN - SCOPUS:85060163845

SN - 0767-3981

VL - 33

SP - 96

EP - 106

JO - Fundamental and Clinical Pharmacology

JF - Fundamental and Clinical Pharmacology

IS - 1

ER -